1. Field of the Invention
This invention relates to basic ethers of 2-benzyl-3-arylbenzofurans, their preparation and use in therapy as antitumour and hypocholesterolemic agents.
2. Description of prior art
A class of triarylethylene derivatives known as the nonsteroidal antiestrogens are now widely used in the treatment of human breast cancer. Their discovery as biological antagonists of estrogen action in the 1950s suggested possible usefulness in the treatment of estrogen responsive diseases. While several such compounds were initially investigated as potential drugs, only tamoxifen, 1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut1-(Z)-ene (Harper et at., U.S. Pat. No. 1,013,907), was approved in the 1970s for the treatment of estrogen receptor (ER)-positive human breast carcinoma on the basis of extensive clinical trials which established its efficacy and low incidence of adverse side effects. Tamoxifen is now the drug of choice for endocrine treatment of all stages of breast cancer in pre- and postmenopausal patients whose tumours are ER-positive. Nonisomerizable antiestrogens such as trioxifene (Jones et al., J.Med.Chem. (1979) 22:962-966) and the benzothiophene antiestrogens (Jones et al., J.Med.Chem. (1984) 27:1057-1066), LY117018 and LY156758, are examples of agents subsequently developed in attempts to improve upon the actions of tamoxifen. Trioxifene, although an effective antiestrogen in clinical trials, possesses greater estrogenic activity than tamoxifen a property that can be expected to reduce its efficacy in estrogen-responsive tumours. The benzothiophene compounds are partial antagonists/agonists (like tamoxifen) but characterized by a shorter duration of action in vivo, a practical disadvantage possibly due to their hydroxylated nature.
The precise mechanism(s) of action of nonsteroidal antiestrogens is not entirely understood although it is clear that a substantial part of their activity depends on the ability of these drugs to interact with the estrogen receptor.
The following well-documented observations however indicate that binding to the estrogen receptor is not the only means by which antiestrogens express biological activity: (1) Antiestrogens also inhibit the proliferation of cells which lack the receptor (Reddel et al., Cancer Res.(1985), 45:1525-1531). (2) Antiestrogen-resistance supervenes clinically, often without any change in the ER status of the resistant tumour (Bloom and Fishman Cancer (1983) 51:1190-1194). (3) Some antiestrogen effects cannot be reversed or prevented by co-administration of estrogen (Sutherland et al., Biochem. Biophys. Res. Commun. (1986) 140:523-529).
More recently, a second high-affinity binding site for antiestrogens distinct from the estrogen receptor has been identified. This intracellular antiestrogen-binding site (AEBS) is present in all mammalian tissues and cell lines thus far examined, including normal human tissues, breast carcinoma and other human tumours and in breast cancer cell lines (Kon, J.Biol. Chem.(1983) 258:3173-3177).